Antibody-drug-conjugate and its use for the treatment of cancer

Abstract

The present invention relates to an antibody-drug-conjugate. From one aspect, the invention relates to an anti-body-drug-conjugate comprising an antibody capable of binding to a Target, said antibody being conjugated to at least one drag selected from derivatives of dolastatin 10 and auristatins. The invention also comprises method of treatment and the use of said anti-body-drag-conjugate for the treatment of cancer.

The invention claimed is: 
     
       1. A method for the treatment of an antigen-expressing cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one antibody-drug-conjugate of the following formula (I):
   A b -(L-D) n    (I)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein: 
 Ab is an antigen antibody or an antigen binding fragment thereof; 
 L is a linker of the following formula (III): 
 
       
         
           
           
               
               
           
         
         wherein: 
         L 2  is (C 4 -C 10 )cycloalkyl-carbonyl, (C 2 -C 6 )alkyl, or (C 2 -C 6 )alkyl-carbonyl, 
         W is an amino acid; 
         w is an integer selected from 0 to 5: 
         Y is p-aminobenzoyloxycarbonyl (PAB-carbonyl) with PAB being 
       
       
         
           
           
               
               
           
         
         y is 0 when w is 0 and y is 1 when w is an integer selected from 1 to 5: 
         the asterisk in formula (III) indicates the point of attachment to D; and 
         the wavy line in formula (III) indicates the point of attachment to Ab; 
         D is a drug moiety of the following formula (II): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or OH; 
         R 2  is (C 1 -C 6 )alkyl, COOH, COO—((C 1 -C 6 )alkyl) or a thiazolyl group: 
         R 3  is H or a (C 1 -C 6 )alkyl group; 
         A is:
 a group of formula -Het-Alk-, wherein Alk is a (C 1 -C x )alkanediyl group and is linked to NR 3 , and Het is a heterocycle optionally substituted by a (C 1 -C 6 )alkyl group and containing at least one nitrogen atom, said nitrogen atom being linked to L, or 
 a group of formula -A a -A b -, wherein A a  is linked to L and is O or NR 9  with R 9  being H or (C 1 -C 6 )alkyl, and A b  is linked to NR 3  and is:
 an aryl-(C 1 -C 8 )alkanediyl or heterocycle-(C 1 -C 8 )alkanediyl group, said group being optionally substituted by a (C 1 -C 6 )alkyl group, the aryl or heterocycle moiety being linked to A a  and the (C 1 -C 8 )alkanediyl moiety being linked to NR 3 ; 
 
 
         the wavy line in formula (II) indicates the point of attachment to L; and 
         n is an integer selected from 1 to 12. 
       
     
     
       2. The method of  claim 1 , wherein the antigen is selected from the group consisting of cluster of differentiation 19 (CD19), cluster of differentiation 20 (CD20), cluster of differentiation 22 (CD22), cluster of differentiation 25 (CD25), cluster of differentiation 30 (CD30), cluster of differentiation 33 (CD33), cluster of differentiation 40 (CD40), cluster of differentiation 56 (CD56), cluster of differentiation 64 (CD64), cluster of differentiation 70 (CD70), cluster of differentiation 74 (CD74), cluster of differentiation 79 (CD79), cluster of differentiation 105 (CD105), cluster of differentiation 138 (CD138), cluster of differentiation 174 (CD174), cluster of differentiation 205 (CD205), cluster of differentiation 227 (CD227), cluster of differentiation 326 (CD326), cluster of differentiation 340 (CD340), mucin 16 (MUC16), glycoprotein Nmb (GPNMB), prostate specific membrane antigen (PSMA), cripto, extra-domain B (ED-B), transmembrane protein with epidermal growth factor like and two follistatin like domains 2 (TMEFF2), ephrin type-B receptor 2 (EphB2), ephrin type-A receptor 2 (EphA2), fibroblast activation protein (FAP), alpha-V integrin (av integrin), mesothelin, epidermal growth factor receptor (EGFR), tumor-associated glycoprotein 72 (TAG-72), disialoganglioside 2 (GD2), carbonic anhydrase 9 (CAIX), 5T4, human epidermal growth factor receptor 1 (HER1), human epidermal growth factor receptor 3 (HER3), human epidermal growth factor receptor 2 (HER2), insulin-like growth factor 1 (IGF-1R), Axl and the extra cellular membrane (ECD) fragment thereof. 
     
     
       3. The method of  claim 1 , wherein the antigen is selected from the group consisting of HER2, IGF-1R, Axl and the extra cellular membrane (ECD) fragment thereof. 
     
     
       4. The method of  claim 1 , wherein said Ab is an antibody or an antigen binding fragment thereof that binds to the human IGF-1R and is selected from the group consisting of: the antibodies 208F2, 212A11, 214F8, 219D6 and 213B10. 
     
     
       5. The method of  claim 1 , wherein said Ab is an antibody or an antigen binding fragment thereof that binds to the human IGF-1R and is: an antibody which comprises the three heavy chain complementarity determining regions (CDRs) of SEQ ID NOs: 1, 2 and 3 and the three light chain CDRs of SEQ ID NOs: 4, 5 and 6. 
     
     
       6. The method of  claim 1 , wherein said Ab comprises:
 a) a heavy chain variable domain (VH) comprising SEQ ID NO: 33 or a variant thereof, wherein said variant comprises the amino acid sequence of SEQ ID NO: 33 with at least 1 back-mutation selected from the residues 20, 34, 35, 38, 48, 50, 59, 61, 62, 70, 72, 74, 76, 77, 79, 82 or 95; and 
 b) a light chain variable domain (VL) comprising SEQ ID NO: 35 or a variant thereof, wherein said variant comprises the amino acid sequence of SEQ ID NO: 35 with at least 1 back-mutation selected from the residues 22, 53, 55, 65, 71, 72, 77 or 87. 
 
     
     
       7. The method of  claim 1 , wherein said Ab is an antibody or an antigen binding fragment thereof that binds to the human protein Axl, said antibody being an antibody comprising the three heavy chain CDRs of SEQ ID NOs: 59, 60 and 61 and the three light chain CDRs of SEQ ID NOs: 56, 57 and 58. 
     
     
       8. The method of  claim 1 , wherein said Ab is an antibody or an antigen binding fragment thereof that binds to the human HER2. 
     
     
       9. The method of  claim 8 , wherein said Ab is trastuzumab. 
     
     
       10. The method of  claim 1 , wherein L 2  is of the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         the asterisk indicates the point of attachment to (W) w ; and 
         the wavy line indicates the point of attachment to the nitrogen atom of the maleimide moiety. 
       
     
     
       11. The method of  claim 1 , wherein w=0; or w=2 and (W) w  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         the asterisk indicates the point of attachment to (Y) y ; and 
         the wavy line indicates the point of attachment to L 2 . 
       
     
     
       12. The method of  claim 1 , wherein L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein the asterisk indicates the point of attachment to D, and the wavy line indicates the point of attachment to Ab. 
       
     
     
       13. The method of  claim 1 , wherein A is a group of formula -A a -A b - in which A a  is as defined in  claim 1  and A b  is a group:
 phenyl-(C 1 -C 2 )alkanediyl, or 
 heterocycle-(C 1 -C 2 )alkanediyl optionally substituted by a (C 1 -C 6 )alkyl group, the heterocycle being a saturated, unsaturated or aromatic ring with 5 or 6 members comprising 1 or 2 nitrogen atoms. 
 
     
     
       14. The method of  claim 1 , wherein A is a group of the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 9  is as defined in  claim 1  and m is an integer selected from 1 to 8, 
         the wavy line indicates the point of attachment to L, and 
         the asterisk indicates the point of attachment to NR 3 . 
       
     
     
       15. The method of  claim 1 , wherein (L-D) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the wavy line indicates the point of attachment to Ab. 
       
     
     
       16. The method according to  claim 1 , wherein the antibody-drug-conjugate is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and the pharmaceutically acceptable salts thereof, 
         wherein Ab is an antigen antibody or an antigen binding fragment thereof. 
       
     
     
       17. The method of  claim 16 , wherein the antigen is selected from the group consisting of CD19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, CD138, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, cripto, ED-B, TMEFF2, EphB2, EphA2, FAP, av integrin, mesothelin, EGFR, TAG-72, GD2, CAIX, 5T4, HER1, HER3, HER2, IGF-1R, Axl and the extra cellular membrane (ECD) fragment thereof. 
     
     
       18. The method of  claim 16 , wherein the antigen is selected from the group consisting of HER2, IGF-1R and Axl. 
     
     
       19. The method of  claim 16 , wherein the antigen is selected from the group consisting of the human HER2, the human IGF-1R and the human protein Axl. 
     
     
       20. The method of  claim 16 , wherein said Ab is selected from the group consisting of:
 a) an Ab or an antigen binding fragment thereof that binds to the human IGF-1R and is selected from the group consisting of: the antibodies 208F2, 212A11, 214F8, 219D6 and 213B10; 
 b) an Ab or an antigen binding fragment thereof that binds to the human IGF-1R and is an antibody which comprises the three heavy chain CDRs of SEQ ID NOs: 1, 2 and 3 and the three light chain CDRs of SEQ ID NOs: 4, 5 and 6; 
 c) an Ab which comprises:
 i) a heavy chain variable domain (VH) comprising SEQ ID NO: 33 or a variant thereof, wherein said variant comprises the amino acid sequence of SEQ ID NO: 33 with at least 1 back-mutation selected from the residues 20, 34, 35, 38, 48, 50, 59, 61, 62, 70, 72, 74, 76, 77, 79, 82 or 95; and 
 ii) a light chain variable domain (VL) comprising SEQ ID NO: 35 or a variant thereof, wherein said variant comprises the amino acid sequence of SEQ ID NO: with at least 1 back-mutation selected from the residues 22, 53, 55, 65, 71, 72, 77 or 87: 
 
 d) an Ab or an antigen binding fragment thereof that binds to the human protein Axl and is an antibody which comprises the three heavy chain CDRs of SEQ ID NOs: 59, 60 and 61 and the three light chain CDRs of SEQ ID NOs: 56, 57 and 58; and 
 e) an Ab or an antigen binding fragment thereof that binds to the human HER2 and is selected from the group consisting of trastuzumab and pertuzumab. 
 
     
     
       21. The method of  claim 1 , wherein n is 2. 
     
     
       22. The method of  claim 1 , wherein n is 4. 
     
     
       23. The method of  claim 1 , wherein said antigen-expressing cancer is selected from the group consisting of breast cancer, colon cancer, esophageal carcinoma, hepatocellular cancer, gastric cancer, glioma, lung cancer, melanoma, osteosarcoma, ovarian cancer, prostate cancer, rhabdomyosarcoma, renal cancer, thyroid cancer, uterine endometrial cancer, mesothelioma, oral squamous carcinoma, Kaposi sarcoma, acute leukemia, colorectal carcinoma, pancreatic ductal adenocarcinoma and any drug resistant cancer. 
     
     
       24. The method of  claim 23 , wherein said antigen-expressing cancer is an HER2-, IGF-1R- or Axl-expressing cancer. 
     
     
       25. A method for the treatment of an antigen-expressing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising at least one antibody-drug-conjugate of the following formula (I):
   A b -(L-D) n    (I)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 Ab is an antigen antibody or an antigen binding fragment thereof; 
 L is a linker of the following formula (III): 
 
       
         
           
           
               
               
           
         
         wherein: 
         L 2  is (C 4 -C 10 )cycloalkyl-carbonyl, (C 2 -C 6 )alkyl, or (C 2 -C 6 )alkyl-carbonyl, 
         W is an amino acid; 
         w is an integer selected from 0 to 5: 
         Y is p-aminobenzoyloxycarbonyl (PAB-carbonyl) with PAB being 
       
       
         
           
           
               
               
           
         
         y is 0 when w is 0 and y is 1 when w is an integer selected from 1 to 5; 
         the asterisk in formula (III) indicates the point of attachment to D; and 
         the wavy line in formula (III) indicates the point of attachment to Ab; 
         D is a drug moiety of the following formula (II): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or OH; 
         R 2  is (C 1 -C 6 )alkyl, COOH, COO—(C 1 -C 6 )alkyl) or a thiazolyl group; 
         R 3  is H or a (C 1 -C 6 )alkyl group; 
         A is:
 a group of formula -Het-Alk-, wherein Alk is a (C 1 -C x )alkanediyl group and is linked to NR 3 , and Het is a heterocycle optionally substituted by a (C 1 -C 6 )alkyl group and containing at least one nitrogen atom, said nitrogen atom being linked to L, or 
 a group of formula -A a -A b -, wherein A a  is linked to L and is O or NR 9  with R 9  being H or (C 1 -C 6 )alkyl, and A b  is linked to NR 3  and is:
 an aryl-(C 1 -C 8 )alkanediyl or heterocycle-(C 1 -C 8 )alkanediyl group, said group being optionally substituted by a (C 1 -C 6 )alkyl group, the aryl or heterocycle moiety being linked to A a  and the (C 1 -C 8 )alkanediyl moiety being linked to NR 3 ; 
 
 
         the wavy line in formula (II) indicates the point of attachment to L; and 
         n is an integer selected from 1 to 12. 
       
     
     
       26. The method of  claim 25 , wherein the composition further comprises a pharmaceutically acceptable vehicle.